Pharmaceutical composition for topical application

ABSTRACT

A pharmaceutical composition comprises a solution having a pH of from 5 to 7.5, including loratadine and/or desloratadine. The composition is suitable for treatment of e.g. allergic rhinitis and allergic conjunctivitis.

The present invention concerns a pharmaceutical composition for topical application. In particular, the present invention concerns a pharmaceutical composition which is suitable for nasal mucosa administration.

Aqueous pharmaceutical compositions for nasal administration comprising solutions of loratadine are disclosed in WO-A-04082589 and solutions of loratadine and desloratadineare disclosed in WO-A-03101434. The nasal pharmaceutical compositions disclosed in these prior art references comprise relatively low levels of antihistamine in solution.

It is an object of the present invention to provide nasal pharmaceutical compositions which may comprise relatively higher amounts of antihistamine in solution than the prior art solutions but which do not demonstrate increased mucosa irritation.

In accordance with the present invention, there is provided a pharmaceutical composition comprising an aqueous solution having a pH of from 5 to 7.5, preferably from 5 to 7, comprising:

Component Amount (wt %) Example a) At least one antihistamine selected 0.02-0.1  from Loratadine and Desloratadine and their pharmaceutically acceptable salts b) At least one polyethylene glycol 5.0-15.0 PEG 200, PEG 300, PEG 400, with a molecular weight of from 100 PEG 600: PEG 400 is to 600 g/mole (co-solvent) preferred c) Propylene glycol (co-solvent) 5.0-15.0 d) At least one non-ionic ethylene 1.0-10.0 Lutrol F127 - (non-ionic oxide/propylene oxide (EO/PO) EO/PO block copolymer with block copolymer with weight average Mw of about 12,500) molecular weight (Mw) from 10,000 to 15,000 (solubilizer) e) polyoxyethylene (20) sorbitan 0.5-5.0  Tween 20, Tween 80: Tween monolaurate and/or polyoxyethylene 80 (polyoxyethylene (20) (20) sorbitan monooleate (solubilizer) sorbitan monooleate) is preferred f) Stabilizer for antihistamine, 0.05-0.5  Salts of EDTA, salts and preferably a chelator stabilizer esters of gallic acid, salts and esters of ascorbic acid, salts of metabisulfite, cysteine and derivatives thereof: Stabilizers which are chelators for the antihistamine are preferred. Alkali salts are preferred e.g. Na₂EDTA Other optional additives <20 Sorbitol, glycerine Water balance to 100.0%

Lutrol is a trademark of BASF SE.

Tween is a trademark of Uniquema Americas LLC.

In one embodiment of the present invention, the pharmaceutical composition comprises an aqueous solution having a pH from 5 to 7.5 comprising:

Component Amount (wt %) Example Loratadine or a pharmaceutically 0.02-0.1  acceptable salt thereof At least one polyethylene glycol with a 5.0-15.0 PEG 200, PEG 300, molecular weight of from 100 to 600 g/ PEG 400, PEG 600 mole (co-solvent) Propylene glycol (co-solvent) 5.0-15.0 At least one non-ionic EO/PO block 1.0-10.0 Lutrol F127 - Mw copolymer with weight average molecular 12,500 weight (Mw) from 10,000 to 15,000 (solubilizer) polyoxyethylene (20) sorbitan 0.5-5.0  Tween 20, Tween 80, monolaurate and/or polyoxyethylene (20) sorbitan monooleate (solubilizer) Stabilizer 0.05-0.5  Salts of EDTA, salts and esters of gallic acid, salts and esters of ascorbic acid, salts of metabisulfite, cysteine and derivatives thereof Other optional additives <20 Sorbitol, glycerine Water balance to 100.0%

A particularly preferred pharmaceutical composition of this embodiment comprises an aqueous solution having a pH from 5 to 7 comprising:

Component Amount (wt %) Loratadine or salt thereof 0.06 PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/PO block copolymer with 5.0 weight average molecular weight (Mw) of about 12,500 Polysorbate 80 1.8 Na₂EDTA 0.1 Water balance to 100.0%

In another embodiment of the present invention, the pharmaceutical composition comprises an aqueous solution having a pH from 5 to 7.5 comprising:

Component Amount (wt %) Example Desloratadine or a pharmaceutically 0.02-0.1  acceptable salt thereof At least one polyethylene glycol with a 5.0-15.0 PEG 200, PEG 300, molecular weight of from 100 to 600 g/ PEG 400, PEG 600 mole (co-solvent) Propylene glycol (co-solvent) 5.0-15.0 At least one non-ionic EO/PO block 1.0-10.0 Lutrol F127 - Mw copolymer with weight average molecular 12,500 weight (Mw) from 10,000 to 15,000 (solubilizer) polyoxyethylene (20) sorbitan monolaurate 0.5-5.0  Tween 20, Tween 80, and/or polyoxyethylene (20) sorbitan monooleate (solubilizer) Stabilizer 0.05-0.5  Salts of EDTA, salts and esters of gallic acid, salts and esters of ascorbic acid, salts of metabisulfite, cysteine and derivatives thereof Other optional additives <20 Sorbitol, glycerine Water balance to 100.0%

A particularly preferred pharmaceutical composition of this embodiment comprises an aqueous solution having a pH from 5 to 7 comprising:

Component Amount (wt %) Desloratadine or salt thereof 0.06 PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/PO block copolymer 5.0 with weight average molecular weight (Mw) 12,500 Polysorbate 80 1.8 Na₂EDTA 0.1 Water balance to 100.0%

In comparison to the prior art formulations, by using a combination of the four components b), c), d) and e), pharmaceutical compositions of the present invention contain higher dosage levels of antihistamine in solution but overall lower dosages of potential irritants. For example, if component b) was eliminated, higher levels of component c) would be required to solubilise the antihistamine, and visa-versa: higher levels of b) or c) on their own in the composition causes irritation on the nasal mucosa, which in turn leads to a reduction the time the composition may be effective. Similarly, if component d) was eliminated, higher levels of component e) would be required to solubilise the antihistamine, and visa-versa: higher levels of d) or e) on their own in the composition causes irritation on the nasal mucosa, which in turn leads to a reduction the time the composition may be effective.

The pharmaceutical composition of the present invention may contain, in addition to co-solvents b) and c), one or more other co-solvents, such as sorbitol and glycerine, but such co-solvents should be used at non-irritating levels.

The pharmaceutical composition of the present invention may contain, in addition to co-solubilizers b) and c), one or more other co-solubilizers, but such co-solubilizers should be used at non-irritating levels.

The stabilizer is preferably a chelator for the antihistamine.

The aqueous solution may require pH adjustment to the range 5 to 7.5, preferably 5 to 7. This can be achieved readily by a person skilled in the art. For example, if the pH of the solution is lower than 5, then the pH may be raised by the incorporation of an appropriate amount of alkali, such as NaOH solution.

The pharmaceutical composition is especially suitable for nasal administration, for example for the treatment of allergic rhinitis, though it may also be suitable for ocular administration, for example for the relief of allergic conjunctivitis.

The invention in its various embodiments shall now be further described by way of exemplification only:

A pharmaceutical composition according to the present invention was prepared as follows:

10.0 parts by wt PG (Propylene Glycol) and 10.0 parts by wt PEG₄₀₀ (Macrogol 400) are mixed. The amount of 0.06 parts by wt Loratadine is dissolved in the obtained mixture to obtain Solution A.

Separately, 5.0 parts by wt Lutrol F127 (Poloxamer 407), 1.8 parts by wt Tween 80 (Polysorbate 80) and 0.1 parts by wt Na₂EDTA are dissolved in 70 parts by wt purified water, preheated to 60° C., to obtain Solution B.

Solution A is added to Solution B at constant stirring to obtain Solution C.

Solution C is adjusted as necessary to pH 5,5 with 1M solution of Sodium Hydroxide and is complemented to a total of 100 parts w/w with purified water to obtain the final composition.

The composition is as shown in Table 1.

TABLE 1 Component Amount (wt %) Loratadine 0.06 active drug PEG 400 10.0 co-solvent PG 10.0 co-solvent Lutrol F127 5.0 solubilizer Tween 80 1.8 solubilizer EDTA 0.1 stabilizer (chelator) Water balance to 100.0% —

The pharmaceutical composition has the characteristics shown in Table 2:

TABLE 2 Appearance clear, colorless pH 5.5 Density at 20° C. p_(s) = 1.0273 at 25° C. p_(s) = 1.0251 Dynamic at 20° C. η = 54.57 · (2.4100 − 1.0273) · 0.07752 = viscosity η, 5.84 mPa · s at 25° C. η = 45.93 · (2.4100 − 1.0251) · 0.07752 = 4.93 Loratadine  0.06 content Na₂EDTA 0.1 content 

1. A pharmaceutical composition comprising an aqueous solution having a pH of from 5 to 7.5 comprising: Component Amount (wt %) a) At least one antihistamine selected 0.02-0.1  from Loratadine and Desloratadine and their pharmaceutically acceptable salts b) At least one polyethylene glycol 5.0-15.0 with a molecular weight of from 100 to 600 g/mole c) Propylene glycol 5.0-15.0 d) At least one non-ionic ethylene 1.0-10.0 oxide/propylene oxide (EO/PO) block copolymer with weight average molecular weight (Mw) from 10,000 to 15,000 e) polyoxyethylene (20) sorbitan 0.5-5.0  monolaurate and/or polyoxyethylene (20) sorbitan monooleate f) Stabilizer 0.05-0.5  Other optional additives <20 Water balance to 100.0%


2. A pharmaceutical composition as claimed in claim 1 which comprises an aqueous solution having a pH from 5 to 7.5 comprising: Component Amount (wt %) Loratadine or a pharmaceutically 0.02-0.1  acceptable salt thereof At least one polyethylene glycol with 5.0-15.0 a molecular weight of from 100 to 600 g/mole Propylene glycol (co-solvent) 5.0-15.0 At least one non-ionic EO/PO block 1.0-10.0 copolymer with weight average molecular weight (Mw) from 10,000 to 15,000 polyoxyethylene (20) sorbitan 0.5-5.0  monolaurate and/or polyoxyethylene (20) sorbitan monooleate Stabilizer 0.05-0.5  Other optional additives <20 Water balance to 100.0%


3. A pharmaceutical composition as claimed in claim 2 which comprises an aqueous solution having a pH from 5 to 7 consisting of: Component mount (wt %) Loratadine or a pharmaceutically 0.06 acceptable salt thereof PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/PO block 5.0 copolymer with weight average molecular weight (Mw) of about 12,500 Polysorbate 80, 1.8 Na₂EDTA 0.1 Water balance to 100.0%


4. A pharmaceutical composition as claimed in claim 1 which comprises an aqueous solution having a pH from 5 to 7.5 comprising: Component Amount (wt %) Desloratadine or a pharmaceutically 0.02-0.1  acceptable salt thereof At least one polyethylene glycol with 5.0-15.0 a molecular weight of from 100 to 600 g/mole Propylene glycol 5.0-15.0 At least one non-ionic EO/PO block 1.0-10.0 copolymer with weight average molecular weight (Mw) from 10,000 to 15,000 polyoxyethylene (20) sorbitan 0.5-5.0  monolaurate and/or polyoxyethylene (20) sorbitan monooleate Stabilizer 0.05-0.5  Other optional additives <20 Water balance to 100.0%


5. A pharmaceutical composition as claimed in claim 4 which comprises an aqueous solution having a pH from 5 to 7 consisting of: Component Amount (wt %) Desloratadine or a pharmaceutically 0.06 acceptable salt thereof PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/PO block 5.0 copolymer with weight average molecular weight (Mw) of about 12,500 Polysorbate 80, 1.8 Na₂EDTA 0.1 Water balance to 100.0% 